J. Org. Chem. 1992,57,6067-6071 run 14
15 16
Table 111. Kinetic Data for the Reaction of 0-1 with klb ( k , + k,')bf 0.13 2.2 0.10 (0.09) 0.22 0.15 0.08 (0.05) 0.15 0.07 (0.07)
[o-lln,M quantity of MnO,"
0.040 0.026 0.090
6067
MnOJTHF at 45 "C KCS
2.6 2.7 2.8
(k,lk,'P
k,b*
1.6
0.135
(k,')b* 0.084
1.4 1.2
1.4 & 0.2 0.08 i 0.02 2.7 f 0.1 Expressed in (moles of Mn02 added/L of original reaction mixture). *Rate constants kl, kz,and k2/ are in units of lo4 M-' s-'. e Error limits are standard deviations. dValuesin parentheses calculated with the method in ref 11. eMean of a point-by-point K. fcalculated from k2 + k; = Kkl. #Mean of a point-by-point K (=[5]/[0-2]). *Calculated from kz + k2/ and k2/k2/. 'Mean of a point-by-point kz/k2/ (=[o31K/[61).
av
Table IV. Bond Dissociation Energies of Benzylic C-H Bonds from Extended Huckel Calculations comud BDE,eV compd BDE,eV 0- 1 4.33 m-2 5.31 0-2 4.94 P-1 5.31 5 5.98 P-2 5.02 m- 1 5.18 withdrawn every 2-6 h, fiitered, diluted with water, and analyzed by HPLC (or filtered, evaporated, dissolved in acetone-d6/TMS and analyzed by 'H-NMR spectroscopy). Absolute concentrations of 1 (or 4), 2, and 3 (or benzaldehyde) were determined from HPLC or 'H-NMR integrations (corrected for response factors) and the known initial concentration of the alcohol. The unreacted amount of Mn02 at each analysis time was calculated from ita known initial mount less the total mount of aldehyde product(s) formed. Thus in the reaction of benzyl alcohol (moles of Mn02/L of original reaction mixture) = (initialmoles of Mn02/L of original reaction mixture) - [benzaldehyde]and in the reaction of the diols (moles of Mn02/L of original reaction mixture) = (initial moles of Mn02/L of original reaction mixture) - [2] - 2[3]. The apparent rate constant k for the reaction of benzyl alcohol was determined by a usual second-order rate plot. The determination of the apparent rate constants for the consecutivecompetitive reactions of p-1 and m-1 was performed as before2J by the graphical integration method of Wideqvist.l0 For each data point the value of In ([ llO/[ 11) and 0 (unreacted moles of Mn02/L of original reaction mixture) dt) were determined. The value of kl was found as the slope of a linear plot of In ([l]o/[l]) versus 8. Then for each data point, the value of K ( = k 2 / k 1 )was determined from the equation
The K value for a given run was the mean of the point-by-point K values. From this value, k2 was calculated (k2 = Kkl). The value determined also by a computational method, the details of K w a ~ of which can be found in ref 11. For the kinetic analysis of the reaction of 0-1the concentrations of 0-1,0-2,0-3,5,and 6 were determined from 'H-NMR integrations and the known initial amount of 0-1. The unreacted amount of Mn02was calculated from the equation (moles of Mn02/L of reaction mixture) = (moles of Mn02 initially added/L of reaction mixture) - [o-21 - 2[0-31 - [5] - 2[6]. The value of kl was determined graphically as described above. The K value in this reaction (SchemeIV)defined as K = (k, + k,')/kl was determined from the equation
The numbers in parentheses in the MS spectra are relative abundances. 0-1: 'H NMR20 6 4.31* (t,J = 4.8 Hz, 2 H), 4.71 (d, J = 4.8 Hz, 4 H). For the MS spectrum, see ref 2a. 0-2: 'H NMR2' 6 4.47 (t, J = 5 Hz,1H), 5.03* (d, J = 5 Hz, 2 H), 10.28* (s, 1 H); MS m/z 136 (lo), 135 (13), 119 (13), 118 (97), 92 ( l l ) , 91 (21), 90 (82), 89 (loo), 87 (a), 86 (9), 85 (51, 79 (15), 77 (28), 74 (7), 65 (7), 64 (13), 63 (65), 62 (34), 61 (14), 59 (13),53 (7),52 (7), 51 (25),50 (24),49 (7),43 (5), 40 (8),39 (4% 38 (17), 37 (12). 0-3: 'H NMR226 10.54* (e, 2 H); MS m/z 135 (31, 134 (261, 133 (15), 107 (3), 106 (36), 105 (loo), 79 (2), 78 (19), 77 (99), 76 (13),75 (8),74 (18),73 (4),63 (6),62 (6),61 (4),53 (5),52 (141, 51 (72), 50 (50), 49 (7), 39 (161, 38 ( l l ) , 37 (9). 5: 'H NMR2' 6 4.91 (d, J = 13 Hz, 1H), 5.12* (dd, J1= 2 Hz, J 2 = 13 Hz, 1H), 5.58 (d, J = 7.5 Hz, 1H), 6.41 (dd, 5 1 = 2 Hz, J2 = 7.5 Hz, 1 H); MS m/z 119 (12), 118 (96), 91 (5), 90 (63), 89 (loo), 87 (14), 86 (8), 85 (4), 64 (12), 63 (54), 62 (25), 61 (12), 59 (17), 51 (lo), 50 (13), 43 (12), 41 (8),40 (5), 39 (37), 38 (16), 37 (12). 6 'H NMRDvUb6 5.36* (s,2 H); MSN m/z 134 (331,133 (161, 106 (29), 105 (85), 89 (8), 78 (181, 77 (1001, 76 (141, 75 (lo), 74 (19), 73 (7), 63 (lo), 62 (8), 61 (6), 53 (8), 52 (16), 51 (71), 50 (48), 49 (9), 39 (19), 38 (13), 37 (13).
Acknowledgment is made to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research. Also, we thank the Research Council of the University of Cincinnati for a summer fellowship to I.C. (20) Pouchert, C.; Campbell, J. R. The Aldrich Library of NMR Specta; Volume 5, 7c; Aldrich Chemical Company: 1974. (21) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. SOC. 1986,108,452. (22) Reference 20; Volume 6, 81B. (23) Sadtler Standard Spectra Collection, Volume 45, 27216 M , Sadtler Research Laboratories, 1978. (24) (a) Grasselli, J. G. CRC Atlas of Spectral Data and Physical Constants of Organic Compounds;CRC Press: Cleveland 1973; p 518. (b) Stenhagen,E.; Abrahamson, S.; McLafferty, F. Atlas of Maps Spectral Data; Interscience: New York, 1969; p 649.
Stereoselectivity of the a-Sulfenylation of 4-Phenylbutyrolactone. Configurational and Conformational Analyses by 'H NMR Spectroscopy' h g e l i n a Flores-Para,* Dora M. Gutigrrez-Avella, Ysbrain J. Guzmk-Vhquez, Armando Ariza-Castolo, and Rosalinda Contreras
The K value for a given run was again the mean of the pointby-point K values. Partial 250-MHzproton NMR and mass spectral data of the species involved in this reaction are given below. In each case these data were consistent with previously published lower resolution spectra. Spectra of pure material in acetoneds/TMS were obtained for 0-1and 0-3,whereas the data for 0-2,5, and 6 were obtained by W/MS and 'H-NMR analysis of the reaction mixture after the appropriate treatment. Acetone-d6/TMS was used for all NMR analyses; peaks marked with an asterisk are those used for determining relative amounts of reactants and products. Acetone or THF was used as a solvent for the GC/MS analyses. 0022-3263/92/1957-6067$03.00/0
Departamento de Quimica, Centro de Investigacidn y de Estudios Avanzados del Instituto Polit6cnico Nacional, Apartado Postal 14- 740, Mgxico, D.F.07000, Mexico Received February 27, 1991
y-Butyroladones have emerged as important synthons and building blocks for the synthesis of complex natural produck2 Their stereochemistry and conformational (1)Taken in part from the Master Thesis of D.M.G.-A., Chemistry Department, Cinvestav-IPN Mexico, 1990.
0 1992 American Chemical Society
6068 J. Org. Chem., Vol. 57, No. 22, 1992
Notes
,H3% 5 (R- SC,H5) I
6
7
2 (R- SCH,) (R- CH,)
Figure 1. (a) Sulfenylation: (1) LDA/THF, (2) RSSR. (b) Methylation: (1)LDA/THF, (2) CHJ. behavior are interesting because of their potential as optically active reagentseH Highly diaabreofacialalkylations of electrophilesat C-2 of substituted y-butyrolactonea have been reported, showing that reactions occur preferentially anti to the C-4 s~bstituent."~ Herein, we present our resulta on stereoselective a-sulfenylations of 4-phenylbutyrolactone (1). These reactions are noteworthy because they give a high proportion of the cis isomers: 2-(phenylthio)- or 2-(methylthio)-4-phen ylbutyrolactones (3-cis and 44s). In contrast, the same sulfenylation reactions performed on 2-methyl-4-phenylbutyrolactone(2) as well as methylation of 1 and 3 proceed trans to the phenyl group with high stereoselectivity. The stereochemistq and the conformational equilibria of the substituted butyrolactones are also reported.
Results and Discussion The sulfenyl derivatives were prepared by reaction of the lithium enolates of 4-phenylbutyrolactone (1) and 2-methyl-4-phenylbutyrolactone(2) with diphenyl disulfide or dimethyl disulfide under different reaction conditions as described in the Experimental Section, Figure 1. The reaction of the lithium enolate of 1 with diphenyl disulfide afforded a mixture of cis and trans isomers ( 3 4 s and 3-trans) in a 60/40 ratio. On the other hand, the reaction of the same lithium enolate of 1 with dimethyl disulfide gave a mixture of cis and trans isomers (4-cis and 4-trans) in a 80/20 ratio. We considered it important to understand why the sulfenylation reactions of 1 afforded unexpected proportions of the cis isomers and so decided to analyze the methylation of the enolate of 1 that gives 2-trans and 2 4 s in a 94/6 ratio. These contrasting results eliminate the possibility that the phenyl group acta as a directing group for a cis attack. Another explanation for the stereochemistry of a-sulfenylation is based on a base-catalyzed equilibration of the initially formed a-sulfenyl compounds. In order to check this idea, we treated the isomer mixture of 2-trans and %-cis (94/6%) with lithium diisopropylamide (LDA) followed by hydrolysis at -78 OC and obtained predominantly 2 4 s (90%), indicating that at this temperature the protonolysis of the enolate is diastereoselective and anti to the phenyl group. However, the protonolysis at room temperature loses its stereoselectivity and gives a 46/54 isomer ratio (cis/trans). In order to establish the diastereoselectivity of the (2) (a) Chamberlain R. A.; Dezube M. Tetrahedron Lett. 1982, 23, 3055. (b) Ziegler F. E.; Cain W. T. J. Org. Chem. 1989,54, 3347. (3) Tadano, K.4.; Kanazawa, S.; Ogawa, S.J . Org. Chem. 1988, 53, 3868. (4) Takano, S.; Chiba, K.; Yonaga, M.; Ogasawara,K. J. Chem. Soc., Chem. Commun. 1980,616. (5) Tomioka,K.; Kawasaki, H.; Iitaka, Y.; Koga, K. Tetrahedron Lett. 1986, 803. (6) Fray, A. H.; Kaye, R. L.; Kleinman, E. F. J. Org. Chem. 1986,51, 4828. (7) (a) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. J. Org. Chem. 1988, 53, 4094. (b) Takano, S.; Uchida, W.; Hatakeyama, S.; Ogasawara, K. Chem. Lett. 1982, 733.
cis
(R-CH,, R'-H) 3 (R-SC,H,, R'-H) 4 (R-SCH,, R'-H) 5 (R-SC,H,, R'-CH,)
3 4
trans (R-C6H5) (R-CH,)
R
2-trans
H
5-trans 6-trans 7
(R-sc,H,) (R- SCH,)
(R-CH,)
Figure 2. Configurationand conformation of the studied lactones
protonation of 3, the mixture of 3 4 s and 3-trans was separated by chromatographyon a silica gel column. Each isomer was converted to the enolate with LDA and protonated with a mixture of AcOH/MeOH/THF at -78 OC to give the same isomer ratio (60/40 of cis/trans, respectively). The methyl sulfenylation isomers (4-cis and 4trans, 80/20 ratio) could not be separated, but the mixture was submitted to the same protonation conditions described previously, affording 68/32 ratios of the cis/ trans isomers, respectively. The resulta of the protonations clearly show that the initial products of the sulfenylation reaction undergo base-catalyzed equilibration. The role of the acidic proton at C-2 in the stereochemistry of sulfenylation reaction was investigated through the reaction of the lithium enolate of 2-trans with diphenyl disulfide or with dimethyl disulfide in the reaction conditions mentioned before. The reactions were completely stereoselective,affording the 6-trans or 6-trans isomers. Also, a-methylation of both the 3 4 s and 3-trans isomers was carried out using the lithium enolate anion prepared by reaction with LDA in THF. Each isomer separately afforded a mixture of methylated isomers 6-cis and S-trans in a ratio of 90/ 10. It was observed that sulfenylation and methylation reactions as well as protonation of 2 proceed by attack from the face opposite to the phenyl group. In all these molecules the absence of a proton in C-2 avoids the re-enolization, giving stereoselective substitution trans to the phenyl group. As was reported before for other lactone^,^ it is remarkable that lactone 1 can give both methylated isomers 2-trans or 2-cis in high yield either by direct alkylation or by protonation at low temperature and that both isomers 6-trans or S-cis can be obtained from the methylation and sulfenylation reactions by changing the sequence of the reactions. Sulfenyl derivatives 3 and 4 were found to be stable under acidic conditions at room temperature and several hours at 140 "C in DMSO solution. But 3 4 s or 3-trans can be epimerized at room temperature in a THF solution with diisopropylamineto give a ratio of isomers cis/trans of 60:40. Also the 80:20 mixture of 4 4 s and 4-trans gave, under the same conditions, an isomer ratio of 65~45,evidencing the acidity of the C2-H. Slow crystallization of the mixture (about 2 months) of 3-cis/3-trans (60/40,respectively) yielded pure cis or trans isomers, through an asymmetric transformation of second order? which has been shown to occur when crystabation
J. Org. Chem., Vol. 57, No.22, 1992 6069
Notes
Analysis of the coupling constants of 3-trans gave us the dihedral angles between hydrogen atoms and allows us to (8J)'O propose the structure of the anchored conformation (J(H2-H3a) = 1 Hz, 91'; J(H2-H38) = 7.6 Hz, 33"; J/-l (H3p-H4) = 9.6 Hz, 146") in which the phenylthio group is pseudoaxial and the phenyl group is pseudoequatorial. The predominance of this conformer can be rationalized R' H3. H in terms of the longer C-S bond length compared to the C-C bond which renders the sulfur more stable in the axial J (Hz)/dihedral angles (deg) position than the phenyl group. The coalescence temcompound H9-Hn, H9-HnR Hh-Hd H~R-HI Hh-Hnn perature (-10 "C) of the AB system allowed us to calculate 2-cis 8.6126 15.2/1600 5.3138 10.61156 15.2 the energy for the ring inversion as AG* = 12.9 kcal/mol 7.5154 4.8121 12.7 2-transCA 8.51143 8-5/27 in THF. 13.2 8.6126 11.21160 6.6129 9.91148 3-cisn It is noteworthy that the same compound in c,$6 at 27 13.5 3-transb 1.0191 7.6133 5.9134 9.61146 "C appears in a conformational equilibrium shifted largely 6.6/29 7.9/136 13.8 3-transCgd 4.0153 1.9131 to the conformer observed at -105 "C (THF-ds),which has 13.1 44s" 8.8124 10.91158 6.2131 9.61146 4-t1anSnVd 3.2160 7.6133 6.4130 9.01142 12.6 the sulfenyl group in pseudoaxial position and the phenyl 5-cisn8 1.3123 9.21145 13.9 group in pseudoequatorial position. In this case it is 5-trand 5.3134 10.51155 13.9 reasonable to assume that benzene forms a stacking com5.6136 10.51155 13.9 5-trans' plex with the phenyl group of the molecule, slowing ring 6-tIanS 5.6136 10.71156 13.7 inversion. 6.2132 9.91148 12.8 7 The cis-methylthio compound 4-cis presents the same Same coupling constants in CBDsand CDC1,. * THF-d, at -105 preferred conformation as compound 3-cis, as can be obOC. e CUDB. In conformational equilibrium. e This coupling conserved from data in the table. The corresponding trans an abnormally high value; we have msumed the dihedral stant has lactone (4-trans) was observed in conformational equilib= angle based on examination of Dreiding stereomodels. ~%Iw rium at probe temperature in CDC1, and its coupling 13.2 Hz in CDCI,. fCDC1,. pattern is very similar to that of 3-trans recorded under is slower than the interconvertion rate of isomers. At the same conditions. present, we have not been able to direct the crystallization The lactone 2 4 s was found in the same preferred conto a specific isomer by seeding the isomeric mixture with formation as compounds 3 4 s and 4 4 s . The correcrystals of a pure isomer. sponding 2-trans compound presents a complex 'H NMR In an excess of LDA and methyl iodide the lactone 1 spectrum in THF-de. Addition of C6D8induces complete gave the C-2 dimethylated compound 7; this compound separation of all the lines and thus coupling constants can was very useful in the assignment of the configuration of be obtained. The molecule seems to be frozen in one the methyl derivatives. conformation with the methyl group in pseudoequatorial NMR StereochemicalAnalyses. Particular attention position and the phenyl group in pseudoaxial position. The was placed on elucidating the configuration and confortrans configurationwas established on the basis of coupling mation of all lactones prepared in this work, Figure 2. pattern and was confirmed by a NOESY phase-sensitive This information was deduced from the 'H NMR chemical experiment." shifts and coupling patterns of the spectra as well as from The conformation of 5-cis is locked, according to the 'H dihedral angles calculated from J(H-HIQ (Table I). AdNMR spectrum in CDC1, or C6D6 at 270 MHz. Its conditional information was obtained from J(C-H) and figuration was established by a NOESY experiment which NOESY experiments on the methylated compounds. In shows an interaction between H-4 and the methyl group, some cases the IH NMR spectra in c,$6 showed a strong establishing their proximity and therefore their axial upfield benzene-induced solvent shift effect for all ring position. Also, the methyl group shows interaction with protons, in particular for H-38 which is on the same face H-3a. 3-cis and 5 4 s show the same coupling pattern. as the phenyl group. Improved resolution was attained The NOESY experiment shows that the methyl group in c,$6 which allowed observation of the CH2AB system. of 5-trans interacts with H-38 and that H-4 is next to H-3a. The 'H N M R spectrum of 3-cis shows that the heteroThere is no shielding of the methyl by the phenyl group, cycle exists predominantly in one conformation. The two evidencing that neither of these groups is in axial position. large coupling constants between H-2 and H-3B (11.2 Hz, The coupling pattern again is similar to that of the 3-trans 160")and H-38 and H-4 (9.9 Hz, 148") are indicative of isomer. The NOESY experiment shows for 6-trans that the cis structure (Table I). The data allow us to conclude the methyl group and H-38 are interacting with the phenyl that both substituents are pseudoequatorial, based on group and therefore that it is the trans isomer. The coucalculated dihedral angles between the ring hydrogens and pling constants and chemical shifts support the assignfrom the fact that the alternative conformation with the ment. Compound 7 was found anchored at room temtwo substituents in pseudoaxial position is very unlikely perature. The preferred conformer has the phenyl group and should exhibit smaller coupling constants. in pseudoequatorial position. The 3-trans diastereomer is in conformational equilibrium between two conformers having substituents in Conclusion pseudoaxial and pseudoequatorial positions (in CDC13or It was found that the sulfenylation of 2-methyl-4mF-d8, at 27 "cand at 270 M&). At -90 "C in THF-d8 phenylbutyrolactone and methylation reactions of 4the molecule is frozen and complex coupling patterns are phenylbutyrolactone afford predominantly the trans isoobserved. The assignment of the IH NMR spectra were mers, as was found in other alkylation reactions of &subconfirmed by comparison with the calculated spectrwn.1° Table I. Coupling Constants and Calculated Dihedral Angles Based on Vicinal Hydrogen Coupling Constants
Rw
(8)Eliel, E. L. Stereochemistry of Carbon Compounds; McGraw-Hill Kogakusha, LTD Tokyo, 1962;p 63. (9) Cerda, C. M.; Zepeda, L. G.; Joseph-Nathan, P. Tetrahedron Comp. Method. 1990,3,113.
(10)Clark, M.; Thrasher, J. S. Laocdn PC Program, University of Alabama, Department of Chemistry, Tuscalooea, AL 35486. (11)Andersen, N.H.; Eaton, H. L.;Lai,X.Magn. Reson. Chem. 1989, 27,515.
6070 J. Org. Chem., Vol. 57, No. 22, 1992
stituted y-lactones.' In contrast sulfenylation reactions of 4-phenylbutyrolactone give the cis isomers predominantly, evidently as a result of a base-catalyzed equilibration of the C-2 sulfenylatedlactones. A very interesting observation of a second-order asymmetric transformation of compounds 3-cis and 3-trans was made. A very careful NMR study allowed the configuration and conformation of the lactones to be established.
Experimental Section All melting points are uncorrected. 'H NMR and lSCNMR spectra were recorded at 270 and 67.8 MHz, respectively. The isomeric mixtures were separated using medium pressure column chromatography by using silica gel (60 G) as an adsorbent and hexane-CHzClZ mixtures as the eluent. NMR NOESY spectra were recorded on a JEOL 270-GXS (270 MHz), at 27 "C, using a 90"pulse for 'H, with 64 scam and mixing times of 500 ms, and double FT was performed using FT-POWER with the sine-bell function. The NOESY p b s e n s i t i v e experiment was performed according to ref 11. Phenylsulfenylation of Dihydro-S-phenyl-2(3H)-f~one (4-Phenylbutyrolactone, 1). To a solution of diisopropylamine (0.33 mL, 2.35 mmol) in dry THF (10 mL) was added 0.67 mL of n-butyllithium (2.35 mmol, 3.4 M in THF) at -78 "C under nitrogen. The mixture was stirred for 30 min at this temperature. The lactone 1 (0.346 g, 2.13 mmol) was dissolved in dry THF (5 mL), cooled to -78 "C, and added to the LDA solution, and the reaction mixture was stirred at -78 "C over 30 min. Diphenyl disulfide (0.55 g, 2.56 mmol) was dissolved in 5 mL of THF at -78 "C and was added dropwise to the reaction mixture. After the mixture was stirred at -78 "C for 3 h, the reaction was quenched with 1.0 mL of a cool solution (78 "C) of AcOH/ MeOH/THF (k1:l). The organic phase was extracted with CHC1, (10 mL) and washed with water (4 X 5 mL) and the solvent dried and removed. The crude reaction product was a yellow crystalline powder (0.575 g, 90%) consisting of a 60/40 isomer ratio of cis/trans isomers as established by proton NMR on the bash of the signals of H-2 obtained in CW mode at 90 MHz. Separation of 1g of the reaction mixture by column chromatography afforded 0.55 g ( 5 5 % ) of the known'2 3 4 s and 0.36 g (36%) of 3-trans. Similar reactions but with a different order of addition of the reagents (LDA over the lactone 1) or different stoichiometry of the LDA/lactone (0.51; 1:l; 1.51,respectively) or different dilution or different reaction times afforded the same ratio of isomers.
Notes Dimethyl disulfide (0.22 g, 2.35 mmol) was dissolved in 5 mL of dry THF, at -78 "C, and was added dropwise to the reaction mixture. After the mixture was stirred at -78 OC for 3 h, the reaction was quenched as reported for phenylsulfenylation. The mixture wm extracted with CHC1, (10 mL) and washed with water (4 x 5 mL) and the solvent dried and removed. The crude product was a yellow liquid (0.40 g) that after purification by column chromakgraphy afforded the ch/trans mixture as a viscous liquid (0.28 g, 70% yield). Separation of isomers could not be attained. The mixture was observed diredly by proton N M R and the isomer ratio (80/20 of cis/trans) was measured from the analyses of the signals of H-4.
cis -Dihydro-3-(methylthio)-5-phenyl-2(3H)-furanone (cis-2-(methylthio)-4-phenylbutyrolac~ne, kcis): IR (CHCld 1774 cm-'; lSC NMR (CDCIS)174.96 (C=O), 78.88 (C-4), 43.28 (C-2), 33.77 (C-3),13.88 (methylthio), phenyl group 138.63 (Ci), 128.70 (C ), 128.57 (CJ, 125.38 (Cd ppm; 'H N M R (CDClJ 6 2.21 (3 H, 8, CfH,S), 2.07 (1H, dd, H-36), 2.93 (1H, ddd, H-3a),3.72 (1H, dd, H-2), 5.34 (1H, dd, H-4),7.30 (5 H, m, H-aromatic) ppm. traas-Dihydr0-3-(methylthio)-S-phenyl-2( 3H)-furanone (trams-2-(methylthio)-4-phenylbutyrolactone, 4-trans): IR (CHCl,) 1775 cm-'; '3c N M R (CDC1,) 174.29 (Ca),79.84 (C-41, 41.99 (C-2),38.03 (C-3), 14.58 (methylthio),phenyl group 138.48 (CJ, 128.43 (CJ, 128.31 (CJ, 125.52 (C,) ppm; 'H NMR (CDC13) 6 2.27 (3 H, s, CH,S), 2.48 (1H, dd, H-3@),2.44 (1H, dd, H-3a), 3.52 (1H, dd, H-2), 5.60 (1H, dd, H-4),7.30 (5 H, m, H-aromatic) PPm. Methylation of Dihydro-5-phenyl-2(3H)-furanone (1). A solution of the lactone 1 (0.34 g, 2.13 "01) in 5 mL of dry THF was cooled to -78 "C and added to a solution of LDA prepared as reported before [diisopropylamine(0.33 mL, 2.35 mmol) and n-Buli (0.67 mL, 2.35 mmol, 3.5 M) in 10 mL of THF], and the reaction mixture was stirred at the same temperature over 30 min. Methyl iodide (0.16 g, 2.56 mmol) wm dissolved in 5 mL of dry THF, cooled to -78 "C, and added dropwise to the reaction mixture. After the mixture was stirred at -78 "C for 3 h, the reaction was quenched as reported for the phenylsulfenylation, extracted with CHCl, (10 mL), and washed with water (4 X 5 mL) and the solvent was dried and removed. The crude product was a yellow liquid (0.37 g) that was observed directly by 'H NMR (CW, 90 MHz) and the isomer ratio was measured from the analyses of the signals of H-4. After purification of the reaction mixture by column chromatography, 0.33 g of the trans isomer was obtained (90%). trans -Dihydro-3-methyl-S-phenyl-2(3H)-furanone cis -Dihydro-S-phenyl-3-(phenylthio)-2(3H)-furanone (t~s-2-methyl-kphenylbutyrolactone, 2-trans): IR (CHCld (cis-2-(phenylthio)-4-phenylbutyrolactone, 3-cis): mp 90-93 1768an-';MS m/z (re1intensity) 176 (M+,90),132 (48),117 (loo), OC; IR (KBr) 1775 and 1769 cm-'; 13C NMR (CDCl,) 174.39 105 (aO), 77 (37) 42 (60);'9NMR (CDClS) 179.19 ( C d ) , 78.57 ( C d ) , 79.08 (C-4),46.72 (C-2),38.37 ((2.31, phenyl group 138.32 (C-4),38.92(C-2),34.10(C-3),15.60 (CH,), phenyl group 141.69 (Ci),129.30 (0,128.77 (C ,125.62 (C,), phenylthio group 131.77 (CJ, 129.22 (Co), 128.50 (C,), 125.85 (C,) ppm; 'H NMR (c&) (CJ, 133.83 (CJ, 128.67 ( d , 128.73 (C,) ppm; 'H N M R (CDCIS) 6 1.20 (3 H, d, CH,), 2.11 (1H, ddd, H-30), 2.20 (1H, ddd, H-34, 6 4.07 (1H, dd, H-2), 5.33 (1 H, dd, H-4), 2.97 (1H, ddd, H-Ba), 2.53 (1H, tq,H-2),5.40 (1H, dd, H-4),7.28 (5 H, m, H-aromatic) 2.2 (1 H, ddd, H-3/91; (C&) 6 2.90 (1H, dd, H-2),4.00 (1H, dd, PPm. H-4), 1.54 (1H, ddd, H-3a),1.25 (1H, ddd, H-36). Anal. Calcd Methylation of Dihydro-S-pheny1-3-(phenylthio)-2for CleH1402S: C, 71.08; H, 5.22. Found: C,70.85; H, 5.11. (3H)-furanone (3). The lactone 3 4 s or 3-trans (0.50 g, 1.85 trens-Dihydro-5-phenyl-3-(phenylthio)-2(3H)-furanone "01) in 50 mL of dry THF were maintained and LDA (2 "01) (trans-2-(phenylthio)-4-phenylbutyrolactone, 3-trans): mp at -78 "C for 1.5 h. A solution.of methyl iodide (1.43 mL, 2.30 81-82 "C; IR (KBr) 1777 and 1760 cm-'; lSCNMR (C4D80,-105 mmol) in dry THF (10 mL) was added and the reaction mixture "C) 174.60 (C=O), 80.70 (C-4),45.05 (C-2), 38.47 (C-31, phenyl was stirred for 8 h at -78 "C and then allowed to reach room group 139.42 (CJ, 129.38 (CJ, 128.60 (C ,125.51 (C,), phenylthio temperature before being quenched using a saturated aqueous group 132.94 (Ci), 133.41 (C,,), 128.82 Cm),128.48 (C,) ppm; 'H solution of NH4CL The mixturewas extracted with CH2Cg,dried, NMR (CDClJ 6 3.96 (1H, m, H-2), 5.39 (1H,m,H-4), 2.57 (2 concentrated, and separated by column chromatography. In both H, m, H-3a and H-38); (C4DB0,-105 OC 6 4.38 (1 H, dd, H-2), cases the reaction yield was 97% (0.51 g) and the isomer ratio 5.55 (1H, dd, H-4), 2.54 (1H, ddd, H-3a), 2.65 (1H, ddd, H-36); 90/10 of cis/trans (0.45 and 0.05 g, respectively). (C&) 6 3.51 (1H, dd, H-2), 5.01 (1H, dd, H-4), 2.04 (1H, ddd, cis -Dihydro-3-methyl-S-phenyl-3-(phenylthio)-2(3H)H-3~41.84(1H, ddd, H-38). Anal. Calcd for Cl,$Il4O#: C, 71.08; furanone (cis-2-methyl-2-(phenylthio)-4-phenylbutyroH, 5.22. Found C, 70.98; H, 5.15. lactone, 5-cis): mp 71-73 "C; IR (KBr) 1764 and 1761 cm-'; '8c Methylsulfenylation of Mhydrcr-S-pheny1-2(3H)-furanone NMR (CDCl3) 177.36 (C-O),77.29 (C-4), 52.77 (C-2),43.99 (C-3), (1). A solution of lactone 1 (0.34 g, 2.13 mmol) in 5 mL of dry 23.59 (CH,), phenyl group 138.72 (CJ, 128.62 (Co),129.19, (C,), THF was cooled to -78 "C and added to a solution of LDA 125.60 (C,), phenylthio group 130.36 (CJ, 136.94 (CJ, 129.76 (Cd, prepared as reported before [diisopropylamine (0.33 mL, 2.35 129.19 (C,) ppm; lH NMR (CDCl,) 6 1.65 (3 H, 8, CH3),5.33 (1 "01) and n-BuLi (0.67 mL, 2.35 mmol,3.5 M) in 10 mL of THF], H, dd, H-4), 2.60 (1 H, dd, H-34, 2.40 (1 H, dd, H-36); (C&) and the reaction mixture was stirred at -78 "C over 30 min. 6 1.32 (3 H, s, CHS),4.78 (1H, dd, H-4), 1.96 (1 H, dd, H-34, 2.18 (1H, dd, H-3B). Anal. Calcd for Cl7Hl8o2S: C, 71.80; H, 5.67. Found: C, 71.54; H, 5.61. (12) Iwai, K.; Kosugi, H.;Uda, H.; Kwai, M.Bull. Chem. SOC.Jpn. trans -Dihydro-3-methyl-S-phenyl-3-( phenylthio)-21977, 50, 242.
d3
p'
J. Org. Chem. 1992,57,6071-6075 (3H)-furanone (trans-2-methyl-2-(phenylthio)-4-phenylbutyrolactone, 5-trans): mp 115 OC; IR (KBr) 1762 cm-'; 13C NMR (CDClJ 175.67 (M), 77.78 (C-4), 51.57 (C-2), 46.22 (C-3), 23.43 (CH,), phenyl group 138.56 (CJ, 129.07 (C,), 128.60 (Cp), 125.52 (C,), phenylthio group 129.32 (Ci), 137.25 (C,), 130.21 (CJ, 128.78 (C,) ppm; 'H NMR (CDCl,) 6 1.55 (3 H, s, CH3), 5.52 (1 H, dd, H-4), 2.76 (1 H, dd, H - 3 4 , 2.31 (1 H, dd, H-30); (C,3D6) 6 1.29 (3 H, 8, CH,), 5.37 (1 H, dd, H-4), 2.24 (1 H, dd, H-3a), 1.75 (1 H, dd, H-38). Phenylsulfenylation of trans -Dihydro-J-methyl-Sphenyl-2(3H)-furanone (trans-2-methyl-4-phenylbutyrolactone, 2-trans). A solution of lactone 2 (0.4 g, 2.27 mmol) in 5 mL of dry THF was cooled to -78 OC and added to a solution of LDA prepared as reported before [diisopropylamine (0.33 mL, 2.35 mmol) and n-BuLi (0.67 mL, 2.35 mmol, 3.5 M) in 10 mL of THF], and the reaction mixture was stirred at -78 OC over 1 h. Diphenyl disulfide (0.49 mL, 2.27 mmol) was dissolved in 5 mL of dry THF, cooled to -78 OC, and added dropwise to the reaction mixture. Then, the solution was stirred at -78 OC for 3 h, and the reaction was quenched as reported for phenylsulfenylation of 1. The mixture was extracted with CHC13 (10 mL) and washed with water (4 x 5 mL) and the solvent dried and removed. After separation of the crude product by column chromatography, 0.60 g of 5-trans was obtained (93%). Methylsulfenylation of trans-Dihydro-3-methyl-5phenyld(3H)-furanone (trans -2-Met hyl-4-phenylbutyrolactone, 2-trans). A solution of lactone 2 (0.4g, 2.27 mmol) in 5 mL of dry THF was cooled to -78 OC and added to a solution of LDA prepared ae reported before [diisopropylamine (0.33 mL, 2.35 mmol) and n-BuLi (0.67 mL, 2.35 mmol, 3.5 M) in 10 mL of THF], and the reaction mixture was stirred at -78 OC over 1 h. Dimethyl disulfide (0.22 mL, 2.27 mmol) was dissolved in 5 mL of dry THF, cooled to -78 OC, and added dropwise to the reaction mixture. Then the solution was stirred at -78 OC for 3 h, and the reaction was quenched as reported for phenylsulfenylation. The mixture was extracted with CHC1, (10 mL) and washed with water (4 X 5 mL) and the solvent dried and removed. Purification of the reaction mixture by column chromatography afforded 6-trans as a liquid (3.88 g, 77%).
6071
Synthesis of 1-Amino-1-(aminomethy1)cyclopropaneand Its Monobenzamidest Fabrice Vergne, David J. Aitken, and Henri-Philippe Husson* Laboratoire de Chimie Thlrapeutique, URA 1310 du CNRS, Facultl des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France Received April 20, 1992
An increasing number of therapeutic agents, including antiarrythmic, antipsychotic, and antitumor compounds, have structures which incorporate a 1,f-diaminefunction. As an extension of our program' dealing with the preparation of cyclopropane compounds of biological interest? we required a method for the synthesis of a series of 1,2diaminoethanes in which one of the carbon atoms is incorporated into a cyclopropane ring. Here we report on the preparation of the simplest such compound, the previously unknown 1-amino-1-(aminomethyl)cyclopropane, 1, by a simple and efficient synthetic strategy which allows regiospecific functionalization of either primary amine group. Existing methods for the synthesis of vicinal diamines are rather limited and usually involve the introduction of two nitrogen functions onto a preformed carbon skeleton: We propose an alternative strategy, whereby a variety of target molecules might be constructed from a single CaNz unit, an objective which calls for an ethylenediamine synthon having nonequivalent nitrogen and carbon atom reactivities. A possible candidate was (dibenzy1amino)acetonitrile which can be alkylated with certain electrophiles under strongly basic conditions,1bbut recent observations indicate that this synthon is not applicable to trans -Dihydro-3-methyl-3-(methylthio)-5-phenyl-2- cyclopropane-forming reactions in which 1,a-dibromo(JH)-furanone (trans-2-methyl-2-(methylthio)-4-phenyl- ethane is used as the ele~trophile.~ We adopted instead butyrolactone, 6-trans): IR (CHCl,) 1775 cm-'; 13C NMR the related compound [N-(diphenylmethy1ene)aminol(CDCld 174.98 (W), 77.94 (C-4),46.69 (C-2), 46.41 (C-3), 21.95 acetonitrile, 2, as our 1,2-diamine precursor, since it G o (CH,), 11.96 (methylthio), phenyl group 138.42 (CJ, 128.73 (C,), has the requisite differential reactivity of all four central 128.57 (Cp), 125.53 (C,) ppm; 'H NMR (CDC1,) 6 1.60 (3 H, s, atoms. Synthon 2 was first prepared in 1978 by O'DonCH3), 2.21 (3 H, 8, CHaS), 2.25 (1 H, dd, H-30), 2.57 (1 H, dd, nel158and has been used by his groupb and otherss as a H - 3 4 , 5.63 (1 H, dd, H-4), 7.30 (5 H, m, H-aromatic) ppm. synthetic glycine equivalent in the preparation of a number Protonation Reactions. General Procedure. A solution of of amino acid derivatives. the lactone 3-cis (0.10 g, 0.37 mmol) in 5 mL of THF was cooled to -78 OC and added to a solution of LDA prepared as reported The various approaches to the synthesis of 1 are shown before [diisopropylamine (0.037 g, 0.37 mmol) and n-Buli 1.4 M in Scheme I. Double alkylation of 2 with 1,a-dibromo(0.26mL, 0.37 "01) in 10 mL of THF], and the reaction mixture ethane and base under phase-transfer conditions according was stirred at the same temperature over 1 h under a nitrogen to O'DonneUSbgave the cyclopropane derivative 3. Comatmosphere and quenched at -78 "C with a mixture of AcOH/ plete multiple-bond reduction of 3 with lithium aluminum MeOH/THF (1:l:l). The mixture was extracted with CHCl, (20 hydride was inefficient, giving a mixture of products from mL) and the solvent dried and removed. The crude product was which 4 was isolated only in low yield (36%). A high yield observed directly by proton NMR (90 MHz, CW) and the isomer of diamine 4 was obtained using a borane-tetrahydrofuran ratio measured from the analyses of the signals of H-2 or methyl. complex' which allowed the reaction to go to completion Lactones 3-cis and 3-trans afforded a 60/40 (cis/trans) ratio, without complication from reductive decyanatione8 We whereas the 4 4 s and 4-trans mixture (80/20) gave 68/32, respectively. The reaction of the lactone mixture 2-cis and %trans were intrigued to find, however, that a small amount gave an isomer ratio cis/trans of 90/10. The cis isomer was (15-209'0) of a secondary product was formed, correseparated and analyzed by NMR spectrscopy. sponding to a cyclobutanediamine 7a, which was characcis-Dihydro-3-methyl-5-phenyl-2(3H)-furanone (transterized as its benzamide 7b. 2-methyl-4-phenylbutyrolactone, !&cis): IR (CHC13)1767 cm-'; MS m/z (re1intensity) 176 (M+,90),132 (48),117 (loo),105 (80), 77 (37), 42 (50); 13C NMR (CDClS) 179.64 ((3-0)) 79.60 (C-4), 41.35 (C-2), 36.80 (C-3), 15.40 (CH,), phenyl group 139.88 (CJ, 129.22 (Cd, 128.88 (CJ, 126.18 (C,) ppm; 'H NMFt (C4D80/CJI& 6 1.27 (3 H, d, CH,), 1.78 (1 H, td, H-38), 2.74 (1 H, ddd, H - 3 4 , 2.76 (1 H, qdd, H-2), 5.29 (1 H, dd, H-4), 7.32 (5 H, m, H-aromatic) PPm.
Acknowledgment. We thank Mr. Guillermo Uribe for recording the NMR spectra and Professor R. L. S a n t i k for critical reading.
u
.Ph
7a R=H
Ph
8
7 b R=PhCO
Presented in part at the Fifth International Kyoto Conference on New Aspecta of Organic Chemistry (IKCOC-S),Kyoto, Japan, November 1991. Paper GO-42.
0022-3263/92/1957-6071$03.00f 0 0 1992 American Chemical Society
